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Principal Results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial
Henry R. Black, MD;
William J. Elliott, MD, PhD;
Gregory Grandits, MS;
Patricia Grambsch, PhD;
Tracy Lucente, MPH;
William B. White, MD;
James D. Neaton, PhD;
Richard H. Grimm, Jr, MD, PhD;
Lennart Hansson, MD, PhD;
Yves Lacourcière, MD;
James Muller, MD;
Peter Sleight, MD, DM;
Michael A. Weber, MD;
Gordon Williams, MD;
Janet Wittes, PhD;
Alberto Zanchetti, MD;
Robert J. Anders, PharmD; for the CONVINCE Research Group
JAMA. 2003;289:2073-2082.
ABSTRACT
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Context Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk, but the benefit compared with other drug classes is controversial.
Objective To determine whether initial therapy with controlled-onset extended-release (COER) verapamil is equivalent to a physician's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease.
Design, Setting, and Participants Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed the study before unblinding the results.
Intervention Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic,  -blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed.
Main Outcome Measures First occurrence of stroke, myocardial infarction, or cardiovascular disease–related death.
Results Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease–related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P = .77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease–related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease–related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54 [95% CI, 1.16-2.04]; P = .003). More cardiovascular disease–related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53).
Conclusions The CONVINCE trial did not demonstrate equivalence of a COER verapamil–based antihypertensive regimen compared with a regimen beginning with a diuretic or -blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or -blocker treatment.
INTRODUCTION
The background and scientific rationale, inclusion and exclusion criteria, baseline characteristics, and early blood pressure control data regarding the participants for the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial have been previously published.1-2 CONVINCE was planned in 1994 as a large, simple trial3 to assess the equivalence of controlled-onset extended-release (COER) verapamil and standard therapy in preventing cardiovascular disease–related events. It was also the first prospective study of the timing of acute myocardial infarction (MI), cardiovascular event–related death, and stroke—all of which have their highest incidence during the early morning hours (6 AM to noon).4-5 Planned mean follow-up was 5 years; however the trial was stopped 2 years early by the sponsor for commercial reasons.
METHODS
Study Participants
Participants were randomized from 661 clinical sites in 15 countries.2 All had signed informed consent, were 55 years or older, and had at least 1 other established risk factor (eg, diabetes or cigarette smoker) for cardiovascular disease, in addition to hypertension.1
Study Design
CONVINCE was a randomized, double-blind, active-controlled, multicenter, international clinical trial (Figure 1). One group initially received COER verapamil (Covera-HS in the United States, Chronovera in other countries; Pharmacia Corp, Peapack, NJ), which exerts its major antihypertensive effect 6 to 12 hours after administration.6-7 The active-control group began with either hydrochlorothiazide or atenolol. The choice was made by the investigator prior to randomization, based on which treatment the investigator thought would be more suitable for the individual participant, should the participant be randomized to the atenolol or hydrochlorothiazide group.
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Figure 1. Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial
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The primary objective was to compare the 2 regimens in preventing acute MI, stroke, or cardiovascular disease–related death.1 Major secondary outcomes included (1) an expanded cardiovascular disease end point, which included hospitalization for angina, cardiac revascularization or transplant, heart failure, transient ischemic attack or carotid endarterectomy, accelerated or malignant hypertension, or renal failure in addition to the primary outcome; (2) all-cause mortality; (3) cancer; (4) hospitalization for bleeding (excluding hemorrhagic stroke); and (5) incidence of primary end points occurring between 6 AM and noon.1
The design of CONVINCE assumed 2024 participants would develop a primary end point, which provided 84% power for detecting a 14% difference between regimens at a 2-sided significance level of .05. Estimates of noncompliance to COER verapamil (7.5 in first year; 3% each subsequent year) and lost to follow-up rates (1% per year) were incorporated in the sample size and power calculations. It was estimated that 15 000 participants would have to be enrolled to obtain the 2024 events over a 5-year mean follow-up. The sample size was increased to 16 600 (with a target of 2246 events) when it became apparent early in the study that the withdrawal rate from study medication was greater than initially assumed. Equivalence bounds for the hazard ratio (HR) were prespecified as 0.86 to 1.16.1
The randomization schedule was stratified by site and atenolol or hydrochlorothiazide choice in successive permuted blocks of 2, 4, or 6, selected randomly. Schedules were prepared by the statistical center at the Division of Biostatistics at the University of Minnesota, Minneapolis, and provided only to a contract research organization (Parexel International, Waltham, Mass), which used them to implement a transtelephonic interactive voice response system, whereby participants could be randomized by calling a toll-free number.1
Treatments
Participants received 2 bottles for initial treatment (step 1). One bottle contained tablets, 1 to be taken at bedtime, of either placebo or 180 mg of COER verapamil, which provides plasma levels of verapamil that peak8 at about the same time as the early morning increase in blood pressure, pulse rate, and risk of cardiovascular disease–related events.4-5 The other bottle contained tablets, 1 to be taken each morning, of placebo or 50 mg of atenolol, or 12.5 mg of hydrochlorothiazide. The dose of step 1 medication was doubled if systolic blood pressure remained at or above 140 mm Hg and/or diastolic blood pressure remained at or above 90 mm Hg. If blood pressure still was not controlled after increasing the dose, 12.5 mg of hydrochlorothiazide could be added to either the initial dose of either atenolol or COER verapamil. Or 50 mg of atenolol could be added to the initial dose of hydrochlorothiazide (step 2 treatment). The added drug could also be doubled in dose if needed. All step 1 and 2 drugs were blinded. Any additional antihypertensive agent (except a nondihydropyridine calcium antagonist, thiazide diuretic, or -blocker) could be added as a step 3 medication (nonblinded) if needed. An angiotensin-converting enzyme inhibitor was recommended (but not mandated). The study physician could change doses or medications at any time during follow-up.
All study medication for a participant was obtained by using the interactive voice response system, which provided the appropriate bottles of medication based on the step and dose of treatment the participant was currently taking. Each bottle used in the study was assigned a unique number to maintain blinding.
Data Collection and Monitoring
Participants were seen at least semiannually for blood pressure measurements, treatment dispensing, and end point surveillance. On-site data verification was performed at least annually by the contract research organization. An independent data and safety monitoring board met semiannually to review accumulating data. Confidence intervals (CIs) based on the Lan-DeMets version9 of the O'Brien-Fleming group sequential boundaries were used as guidelines for early termination.10 The data and safety monitoring board met 8 times and recommended continuation of the trial after each meeting. All analyses were performed independently of the sponsor by the statistical center at the Division of Biostatistics at the University of Minnesota. All study investigators and the study sponsor were blinded to all between-treatment comparisons until completion of end point data collection and review.
The sponsor closed the study 2 years earlier than originally planned for commercial reasons. A common calendar date of December 31, 2000, was chosen through which all participants would be followed up. Clinical sites were asked to verify the end point status (primary end point and survival status) of each participant as of this date. In addition, in the United States, vital status was determined through the National Death Index for 263 participants whose vital status was unknown through other sources at the end of the trial. Four previously unknown decedents and 15 individuals with previously unknown cause of death were identified as having died from cardiovascular disease.
Primary End Point Review and Adjudication
All possible primary end points were reviewed by an end points committee that was blinded to treatment assignment. This committee consisted of 7 experts in cardiovascular medicine. Two members of the committee independently reviewed documentation provided by the clinical sites for each event to assess whether the event met prespecified criteria. When the 2 reviewers did not agree, the full committee reviewed and adjudicated the case. If documentation was insufficient to confirm (or reject) the event, the site clinician's diagnosis was used. For deaths found only through the National Death Index, the coded cause of death provided was used. Of the 729 participants with a primary event included in the analysis, the end point committee confirmed 651 (89%).
Acute MI required 2 of the following 3 conditions (1) symptoms compatible with acute MI (eg, chest pain) lasting longer than 15 minutes; (2) electrocardiographic changes (new persistent ST-segment elevation or pathological Q waves in 2 contiguous leads); or (3) increased cardiac enzymes (more than twice the upper limit of normal). A diagnosis of stroke required the presence of focal neurological deficit lasting longer than 24 hours. Imaging studies were not required to document a stroke. Any death thought to be compatible with coronary heart disease (eg, heart failure, sudden death) or cardiovascular disease was counted as a cardiovascular disease–related death.
Statistical Methods
Time to event methods (Cox proportional hazards model and Kaplan-Meier curves) were used to compare outcomes for participants randomly assigned COER verapamil with those assigned atenolol or hydrochlorothiazide. Analyses were by modified intent to treat (modified by the exclusion of 2 sites with data integrity concerns), unless otherwise specified, and were stratified by the choice of standard of care and geographic region (United States, Canada, Western Europe, and other [Eastern Europe, Mexico, Israel, or Brazil]) in which the participant's clinical site was located. Analyses of primary and secondary events considered censoring due to losses to follow-up (ie, participants for whom the primary event status was unknown on the closing date), noncardiovascular disease–related deaths (as appropriate), and the closing date of the study. Losses were censored at the date the primary event status was last known (either the date provided by the site during the closeout process; or the date of the last follow-up visit). The HR for COER verapamil vs atenolol or hydrochlorothiazide was estimated from a stratified Cox model with a binary indicator (COER verapamil vs atenolol or hydrochlorothiazide) as the sole covariate. The proportional hazards assumption was tested by including an interaction term between the randomized treatment indicator and log-transformed follow-up time. Heterogeneity of HR for selected prespecified baseline subgroups was assessed by inclusion of an interaction term (randomized treatment by subgroup variable) in the Cox model. To determine whether HRs for the primary end point varied according to time of day of the event, a competing risk analysis was performed for 4 time intervals: midnight to 6 AM; 6 AM to noon; noon to 6 PM; and 6 PM to midnight.11 This analysis allows simultaneous estimation of the HRs for each time interval. The homogeneity of HRs across intervals was tested using a  23 statistic. For the secondary outcome of primary events that occurred between 6 AM and noon, events with other times or unknown times were censored at the date of the event. P values are 2-tailed.
Blood pressure changes from baseline were compared between the 2 treatment groups using the t test. All analyses were performed using SAS statistical software (Version 8.0, SAS Institute Inc, Cary, NC).
RESULTS
Enrollment
Between September 1996 and December 1998, 16 602 participants were randomized. Participants from 2 sites (n = 126; 62 randomized to COER verapamil) were excluded because of data integrity concerns. Thus, our report is based on 16 476 randomized participants (Figure 1). The mean age was 66 years; 56% of participants were women.2 Most participants (84%) had previously been prescribed antihypertensive drugs; hydrochlorothiazide was chosen over atenolol for 7617 (46.2%) participants; 49% had 2 or more risk factors (Table 1).2
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Table 1. Baseline Characteristics of Randomized Groups
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Visit Attendance and Lost to Follow-up Rates
Participants were followed up for at least 2 years and a maximum of 4.25 years; the median follow-up was 3 years. Among the participants who were alive at the time of each visit, attendance was 92% for the COER verapamil group compared with 93% for the atenolol or hydrochlorothiazide group at 12 months; 86% for both groups at 24 months; and 79% for the COER verapamil group compared with 80% for the atenolol or hydrochlorothiazide group at 36 months. On the closing date of the trial, the primary end point status was unknown for 570 participants assigned to the COER verapamil group compared with 563 assigned to atenolol or hydrochlorothiazide (P = .52 by log-rank test for time to lost to follow-up). Corresponding percentages for unknown vital status were 1.5% for COER verapamil and 1.6% for the atenolol or hydrochlorothiazide group (P = .67). In both treatment groups, those lost to follow-up were older; had higher baseline blood pressure levels; were more likely to smoke cigarettes; and have a history of MI, stroke, or transient ischemic attacks compared with participants followed up through the closing date.
Adherence to Study Medication
Median time receiving blinded treatment was 2.2 years for both the COER verapamil group and the atenolol or hydrochlorothiazide group. By the close of the trial, 39.4% of COER verapamil group and 39.7% of the atenolol or hydrochlorothiazide group had discontinued blinded study medication. The proportion was identical for both groups at 1 year (27%). Reasons for withdrawal were available for 78% of those withdrawing in each treatment group. Participants assigned COER verapamil withdrew more often due to adverse signs or symptoms compared with those assigned atenolol or hydrochlorothiazide (P = .02); the most common reason was constipation (216 in the COER verapamil group compared with 28 in the atenolol or hydrochlorothiazide group). However, fewer participants assigned COER verapamil (n = 115) withdrew because of poor blood pressure control (treatment failures) compared with those assigned atenolol or hydrochlorothiazide (n = 207) (P<.001 by log-rank).
Blood Pressure Control and Step of Medication
Both regimens lowered blood pressure significantly.2 Averaged over the entire follow-up period, systolic blood pressure was reduced by 13.6 mm Hg and diastolic blood blood pressure by 7.8 mm Hg from baseline in the COER verapamil group. In the atenolol or hydrochlorothiazide group, systolic blood pressure was reduced by 13.5 mm Hg and diastolic by 7.1 mm Hg. The mean differences in blood pressure change (COER verapamil minus atenolol or hydrochlorothiazide) were small for systolic blood pressure (0.06 mm Hg; 95% CI, -0.44 to 0.56 mm Hg) and diastolic blood pressure (0.67 mm Hg; 95% CI, 0.38-0.95 mm Hg). At the last follow-up visit attended, a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg was achieved in 65.5% of the COER verapamil group and 65.9% of the atenolol or hydrochlorothiazide group.
During follow-up, the prescribed antihypertensive regimen was similar across randomized groups (Figure 2). In both groups, the proportion of participants prescribed more than 1 antihypertensive medication increased with longer follow-up.
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Figure 2. Participants Taking Determined Level of Therapy
Asterisk indicates angiotensin-converting enzyme inhibitor primarily; COER, controlled-onset extended-release. During 6 to 36 months of follow-up, 41 (0.8%) to 105 (1.7%) of participants in either randomized group reported taking no antihypertensive medications.
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At the last visit, 28.4% of the COER verapamil group and 26.1% of the atenolol or hydrochlorothiazide group were taking only the initially assigned medication. The percentages of participants taking step 2 or step 3 treatment or nonblinded medication only were similar between treatment groups. For step 2, 15.5% of the COER verapamil group were receiving treatment compared with 16.1% of the atenolol or hydrochlorothiazide group; step 3, 16.7 vs 18.2%; and no blinded medication, 39.4% vs 39.7%, respectively. Since -blockers, by design, were not used with COER verapamil, the 2 treatment groups differed more with respect to blinded -blocker use (0% of the COER verapamil group vs 43% of the atenolol or hydrochlorothiazide group) than with diuretic use (26% vs 44%, respectively).
Primary End Point and Its Components
There were 364 first primary events in the group randomized to COER verapamil compared with 365 among the atenolol or hydrochlorothiazide group (Table 2). Figure 3 shows the Kaplan-Meier curves for the primary end point. Among those assigned COER verapamil, 1.51% of participants had an event after 12 months of follow-up, 3.12% after 24 months, and 4.94% after 36 months. Among those assigned atenolol or hydrochlorothiazide, 1.69% of participants had an event after 12 months of follow-up, 3.10% after 24 months, and 4.73% after 36 months. The HR for COER verapamil group compared with the atenolol or hydrochlorothiazide group was 1.02 (95% CI, 0.88-1.18; P = .77). There was no evidence that this HR varied over follow-up (proportional hazards P = .36).
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Table 2. Primary and Secondary Events by Treatment Assignment
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Figure 3. Incidence of Primary Outcome Measure Over Time
COER indicates controlled-onset extended-release. The COER verapamil group experienced 364 cardiovascular disease–related events and the atenolol or hydrochlorothiazide group experienced 365 (hazard ratio, 1.02; 95% confidence interval, 0.88-1.18).
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Two supplemental on-treatment analyses were performed. In 1 analysis, follow-up was censored 30 days after blinded study medication was discontinued (220 events among participants in the COER verapamil group compared with 217 events in the atenolol or hydrochlorothiazide group; HR, 1.05 [95% CI, 0.87-1.26]; P = .63). A second analysis included only those participants who were still taking blinded study medication 1 year after randomization. The result of this analysis, which only included events after the first year (171 events among participants in the COER verapamil group compared with 157 in the atenolol or hydrochlorothiazide group), yielded a HR of 1.14 (95% CI, 0.91-1.41; P = .25). After adjusting for age, sex, and risk factors at entry, the HRs were 1.06 (95% CI, 0.88-1.28) using the first on-treatment analysis method and 1.12 (95% CI, 0.90-1.40) using the second on-treatment analysis method.
For fatal or nonfatal MI, the HR was 0.82 (95% CI, 0.65-1.03; P = .09); fatal or nonfatal stroke, 1.15 (95% CI, 0.90-1.48; P = .26); and cardiovascular disease–related death, 1.09 (95% CI, 0.87-1.37; P = .47). Among participants in the COER verapamil group, there were 152 cardiovascular disease–related deaths (24 MIs, 18 strokes, and 110 had other cardiovascular disease). There were 143 cardiovascular disease–related deaths among participants in the atenolol or hydrochlorothiazide group (22 MIs, 21 strokes, and 100 had other cardiovascular disease).
Secondary End Points
The HR for the primary end point or cardiovascular-related hospitalization was 1.05 (95% CI, 0.95-1.16; P = .31) and 1.08 (95% CI, 0.93-1.26; P = .32) for death. Hospitalization for heart failure, a component of the secondary cardiovascular disease end point, was 30% higher with COER verapamil compared with atenolol or hydrochlorothiazide (HR, 1.30; 95% CI, 1.00-1.69; P = .05). More participants assigned COER verapamil (n = 118; 1.4%) than atenolol or hydrochlorothiazide (n = 79; 1.0%) died or were hospitalized for bleeding unrelated to stroke (HR, 1.54; 95% CI, 1.15-2.04; P = .003). Six participants in each group died of hemorrhage not related to stroke (HR, 1.02 [95% CI, 0.33-3.17]; P = .97). Cancer incidence did not vary by treatment group (310 participants reported cancer in the COER verapamil group vs 299 in the atenolol or hydrochlorothiazide group; HR, 1.06 [95% CI, 0.91-1.24]; P = .46). About 14% of participants in each treatment group were hospitalized at least once during follow-up (P = .62).
For the primary end point, treatment HRs did not vary significantly by time of day of the event (P = .43). In each treatment group, more participants had primary events between 6 AM and noon than any other 6-hour period (Figure 4). The HR for the 6 AM to noon events was 1.15 (95% CI, 0.86-1.53; P = .34). For an additional analysis that censored participant follow-up 30 days after blinded medication was discontinued, the HR for events occurring between 6 AM and noon was 1.19 (95% CI, 0.84-1.70).
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Figure 4. Incidence of Primary End Points by Treatment Assignment and Time of Day
Time of onset of first cardiovascular disease–related event was determined for 277 participants in the controlled-onset extended-release (COER) verapamil group and 274 participants in the atenolol or hydrochlorothiazide group. There were 178 (24%) events for which time of onset could not be determined (87 among those randomized to COER verapamil and 91 among those randomized to atenolol or hydrochlorothiazide; hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.73-1.32).
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Baseline-Defined Subgroup Results
When participants were grouped according to baseline characteristics, there was no evidence of a treatment by subgroup interaction for any of the predefined baseline subgroups (Table 3).
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Table 3. Primary Composite End Point by Treatment Assignment
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COMMENT
The results of this study indicate thatCOER verapamil is not equivalent to atenolol or hydrochlorothiazide in preventing cardiovascular disease–related events. The upper bound of the 95% CI for the primary end point (1.18) slightly exceeded the prespecified boundary (1.16) for equivalence of COER verapamil and atenolol or hydrochlorothiazide.1, 12 All HRs involving efficacy were close to 1.0, including the primary end point (1.02), the major secondary combined cardiovascular disease end point (1.05), and mortality (1.08). Similarly, although the HRs increased slightly in the on-treatment analyses for the primary end point, they remained close to 1.0 (1.06 and 1.12). The relative risks for the primary end point did not differ significantly across multiple subgroups (Table 3), including choice of atenolol or hydrochlorothiazide, suggesting that there was no particular baseline characteristic associated with a different outcome overall. Further analyses by choice of atenolol or hydrochlorothiazide that take into account use of treatment steps 2 and 3 are planned. The HR was also close to unity for all of the prespecified secondary cardiovascular disease–related events, with the exception of heart failure. This was expected because both diuretics and -blockers are usually recommended for heart failure,13 whereas verapamil has been associated with an increased risk of heart failure in previous studies.14-15
The treatment regimens showed some minor and statistically nonsignificant differences in the incidence of each component of the primary end point. The incidence of acute MI was about 18% lower with COER verapamil (P = .09) than with the atenolol or hydrochlorothiazide group; this benefit was offset by a 15% higher risk of stroke (P = .26). Although quite possibly due to chance, these trends are consistent with COER verapamil's ability to inhibit platelet aggregation,16-18 leading to both reduced MI incidence and more bleeding. Such a mechanism has been postulated to explain aspirin's tendency to increase hemorrhagic stroke, which is outweighed by a protective effect on MI.19 These trends are opposite to those seen in the Nordic Diltiazem (NORDIL) study, which used the nondihydropyridine calcium antagonist diltiazem.20 A similar contrast is observed when comparing the results of CONVINCE and a recent meta-analysis.21
The prospectively gathered data of Figure 4 confirm previous epidemiological observations concerning the increased risk of cardiovascular events in the early morning hours,4-5 but do not support the concept of chronotherapeutics.22 However, our analyses of this secondary outcome were limited by the smaller than expected number of events, and may be further confounded by nonadherence and use of multiple drugs in each treatment group to control blood pressure.
The findings of CONVINCE are subject to many limitations. The decision to terminate CONVINCE prematurely did not derive from a recommendation of the data and safety monitoring board,23-26 nor from review of external data from other clinical trials.27-28 In this respect, the study is flawed. When stopped, the results were still inconclusive with respect to the prespecified equivalence bounds. Less than a third of the planned number of events were observed, which affects the width of the 95% CIs, and limits the ability to make conclusions about any results (which may not be similar) with longer follow-up. More participants than expected discontinued blinded medication, which pushes the overall result toward the null. Approximately 7% of participants were lost to follow-up for the primary end point. In both treatment groups, participants who were lost to follow-up had baseline risk factors that placed them at a higher risk of cardiovascular disease–related events than participants who continued follow-up. Finally, the effectiveness of atenolol or hydrochlorothiazide in the population studied might differ from that in previous clinical trials establishing the efficacy of atenolol or hydrochlorothiazide, which is a common problem in interpreting the results of equivalence trials.
In summary, CONVINCE was unable to demonstrate equivalence of a COER verapamil–based antihypertensive regimen and a regimen beginning with a diuretic or -blocker. When considered in the context of other trials of calcium antagonists, including the larger Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),29 which found that the calcium channel blocker amlodipine was not superior to the diuretic chlorthalidone, in reducing the rate of coronary heart disease or stroke and was associated with a higher rate of heart failure, these data indicate that the effectiveness of calcium channel blocker therapy in reducing cardiovascular disease–related morbidity and mortality is similar but not better than diuretic or -blocker treatment. These data support the recommendation of the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure30 for low-dose diuretic (or possibly -blocker) therapy for hypertensive patients who have no specific indication for another antihypertensive drug.
AUTHOR INFORMATION
Corresponding Author and Reprints: Henry R. Black, MD, Rush Medical College of Rush University, 1700 W Van Buren St, Suite 470, Chicago, IL 60612 (e-mail: hblack{at}rush.edu).
Financial Disclosures: The following authors have received honoraria for serving as a speaker: Dr Black (Astra-Zeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer/Pharmacia, and Wyeth-Ayerst); Dr Elliott (Abbott Laboratories, Astra Merck Inc, Astra Pharmaceuticals, Astra USA, AstraZeneca Pharmaceuticals, Bayer Pharmaceuticals Co, Bristol-Myers Squibb, Ciba-Geigy Inc, CibaGeneva Pharmaceuticals Inc, ER Squibb & Sons, GD Searle & Co, Glaxo Inc, Hoechst-Marion-Roussel, ICI Pharma, Key Pharmaceuticals, Knoll Pharmaceuticals, Kos Pharmaceuticals, Marion Merrell-Dow, Merck Human Health, Merck Sharp & Dohme, Monsanto, Neurex Inc, Novartis Pharmaceuticals Corp, Parke-Davis Inc, Pharmacia, Pfizer Inc, Procter & Gamble, Sandoz Inc, Schwarz Pharmaceuticals, Syntex Inc, Solvay Pharmaceuticals Inc, Upjohn Co, Unimed Pharmaceuticals, Wyeth-Ayerst Inc, Zeneca Inc); Dr Sleight (Abbott, AstraZeneca, Aventis, Bayer, Boehringer-Ingelheim, Boehringer Mannheim, Bristol-Myers Squibb Inc, Genentech, GlaxoSmithKline, Knoll, Menarini, Merck, Monarch, Novartis, Pfizer, Pharmacia, Sanofi, Servier); and Dr Weber (Pharmacia).
The following authors have received funding/grant support for research projects: Dr Black (Bristol-Myers Squibb, Boeringer, Merck, Merck Sharp & Dohme, Pfizer/Pharmacia); Dr Elliott (Smith, Kline & French Laboratories, Glaxo Inc, GD Searle & Co, Abbott Laboratories, Bristol-Myers Squibb Inc, Merck Human Health, Wyeth-Ayerst Inc, Hoechst Marion-Roussel, SmithKline Beecham Inc, Boehringer-Ingelheim Inc, Pfizer Inc, Knoll Pharmaceuticals, Sankyo Pharmaceuticals, Astra-Merck Inc); Mr Grandits (Searle, Pharmacia); Dr Grambsch (Searle, Pharmacia); Dr Lucente (Searle, Pharmacia); Dr Neaton (Searle, Pharmacia); Dr Grimm (Searle, Pharmacia); Dr Hansson (Searle, Pharmacia); Dr Lacourcière (Searle, Pharmacia); Dr Muller (Pharmacia); Dr Sleight (AstraZeneca, Aventis, Boehringer-Ingelheim, Bristol-Myers Squibb Inc, GlaxoSmithKline, Monarch, Merck, Roche); Dr Weber (Pharmacia); Dr White (Searle, Pharmacia); Dr Wittes (Pharmacia); Dr Zanchetti (GD Searle & Co, AstraZeneca, Merck Sharp & Dohme, Novartis, GlaxoSmithKline).
The following authors have served as a consultant/advisor: Dr Black (Abbott, Astra-Zeneca, Biovail, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck Sharp & Dohme, Pfizer/Pharmacia); Dr Elliott (Smith, Kline & French Laboratories, GD Searle & Co, Curative Technologies Inc, Bristol-Myers Squibb Inc); Dr Weber (Pharmacia) Dr Williams (GlaxoSmithKline, Pharmacia, Merck, Novartis); Dr Zanchetti (GD Searle & Co, AstraZeneca, Merck Sharp & Dohme, Novartis, GlaxoSmithKline).
Author Contributions: As principal investigator of CONVINCE, Dr Black had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Black, Elliott, Lucente, White, Neaton, Grimm, Hansson, Muller, Sleight, Weber, Williams, Wittes, Zanchetti.
Acquisition of data: Black, Elliott, Lucente, White, Neaton, Grimm, Lacourcière, Sleight, Zanchetti, Anders.
Analysis and interpretation of data: Black, Elliott, Grandits, Grambsch, White, Neaton, Grimm, Hansson, Sleight, Weber, Zanchetti, Anders.
Drafting of the manuscript: Black, Elliott, Neaton, Sleight, Weber.
Critical revision of the manuscript for important intellectual content: Black, Elliott, Grandits, Grambsch, Lucente, White, Neaton, Grimm, Hansson, Lacourcière, Muller, Sleight, Weber, Williams, Wittes, Zanchetti, Anders.
Statistical expertise: Grandits, Grambsch, Neaton, Wittes.
Obtained funding: Black, Lucente, Muller, Weber, Williams, Anders.
Administrative, technical, or material support: Black, Elliott, Lucente, White, Grimm, Hansson, Sleight, Weber, Zanchetti, Anders.
Study supervision: Black, Elliott, Lucente, White, Grimm, Hansson, Lacourcière, Sleight, Zanchetti, Anders.
CONVINCE Executive Committee: Henry R. Black, MD, chair (primary principal investigator); Robert J. Anders, PharmD; Tracy Lucente, CONVINCE senior project director; Richard H. Grimm, Jr, MD, PhD, Lennart Hansson, MD, PhD, Yves Lacourcière, MD, James Muller, MD, James D. Neaton, PhD, Peter Sleight, MD, Michael A. Weber, MD, William B. White, MD, Gordon Williams, MD, Janet Wittes, PhD, Alberto Zanchetti, MD, and a contract research organization representative.
End Points Committee: William B. White, MD, chair; William C. Cushman, MD, William A. Frishman, MD, Norman K. Hollenberg, MD, PhD, Thomas G. Pickering, MD, DPhil, Thomas R. Price, MD, Dominic A. Sica, MD.
Publications and Ancillary Studies Committee: Richard H. Grimm, Jr, MD, PhD, chair; Stephen P. Glasser, MD, Gregory M. Grandits, MS, Suzanne Oparil, MD, Ronald M. Prineas, MBBS, PhD, Carolyn Kong.
Data Safety and Monitoring Board: Lawrence S. Cohen, MD, chair; Lawrence M. Brass, MD, David DeMets, PhD, Charles K. Francis, MD, Daniel M. Kolansky, MD, Richard C. Pasternak, MD.
Principal Investigators (by country, with country leader listed first): Brazil: Decio Mion, Jr; Fernando Antonio de Almeida; Iran Castro; Paulo Cesar B. Viega Jardim; Osvaldo Kohlman; José Joaquim Fernandes Rapozo Filho; Salvador Rassi; José Márcio Ribeiro; Antonio Silveira Sbissa.
Bulgaria: Tihomir Dascalov; Nikolai Djurdjev; Anna Elenkova; Mladen Grigorov; Vallentina Grigorova; Roumiana Kermova-Grogorova; Christo Kojukharov; Georgi Kussitasev; Svoboda Lovdjieva; Stefan Mantov; Choudomir Nachev; Nikolay Penkov; Svetla Torbova; Christo Blagoev Tsekov.
Canada: Yves Lacourcière; Carl Abbott; Michael Alexander; Don Allan; Ronnie Aronson; John Atherstone; Marie-Claude Audet; Murray Awde; Gordon Bailey; Robert Beattie; Michael Bentley-Taylor; Bruno Bernucci; Peter Bolli; Remi Bouchard; Ted Brankston; Ellen Burgess; Mathew Burnstein; Denis Callaghan; J. Harry Callaghan; Douglas Carmody; Richard Casey; Josette Castel; Martyn Chilvers; Paolo Costi; Benoit Coulu; David Crowley; I. Dan Dattani; John Davies; Jacquest de Champlain; Eric Deemsted; Sanjay Dhingra; Frank Doane; Peter Dzongowski; Connie Ellis; Neil Filipchuk; Daniel Garceau; Roger Hamilton; Paul Handa; Roy Harding; Kenneth Heaton; Breet Hennefant; James Hii; Kkandker Hoque; Marc Houde; William Hughes; Jamie Hynd; Saul Isserow; Christopher Janz; Martin Juneau; David Kendler; Carter Kennedy; Mahesh Khurana; Jan Kornder; Simon Kouz; Christopher Lai; Daniel Landry; Hugh Langley; Pierre Larochelle; Claude Lauzon; Jacobson Le Roux; Roland Leader; Monique LeBlanc; Larry Leiter; Jacquest Lenis; Richard Lewanczuk; John Li; Robert Luton; Patrick Ma; Jonathan MacKenzie; Jamuna Makhija; Dan Malone; Jean-Marie Martel; Murray Matangi; Grant Matheson; Guiseppe Mazza; Tom McAvinue; Sheila McGrath; William McKeough; Jeanne McNeill; Pravine Mehta; Adrien Melanson; Karim Merali; Phil Morris; Robert Morrison; Shah Nawaz; Robert Nitkin; S. John Nuttall; Brian O'Kelly; William O'Mahony; Robert Orchard; Yves Pesant; Robert Petrella; Denis-Carl Phaneuf; Eric Poulin; Brendan Quinn; J. Lloyd Reddington; Maurice Roy; Terrance Ruddy; Luis Salgado; Michel Sauve; Daniel Savard; Gulshan Sawhney; Larry Schmidt; Vyta Senikas; Daniel Shu; Duncan Sinclair; Randell Smith; David Spence; Richard St-Hilaire; James A. Stone; Bruno St-Pierre; Jim Swan; Paul Talbot; Kim-Weng Tan; Sheldon Tobe; Luc Trudeau; Alain Vanasse; Pradeep K. Vohora; Lorne Weiner; Richard Whatley; Paul Whitsitt; Mark Wilkinson; Noel Wright; Henry Wu.
Czech Republic: Milena Kubickova; Renata Cifkova; Ivan Gregar; Petr Jansky; Helena Nemcova; Petr Petr; Ivana Popdrapska; Borivoj Semrad; Jarmila Siegelova; Miroslav Soucek; Zdenek Vomacka; Eva Zidkova.
Germany: Roland Schmieder; Holger Kinkernagel; Stefan Gesenhues; Ranier Häge; Jürgen Steinhauer; Henning Wiswedel; Wolfram Zingler.
Hungary: Csaba Farsang; Miklos Csanady; Istvan Edes; Katalin Fugedi; Tamas Gexatesi; Czuriga Istvan; Tarjan Jeno; Ilona Pap; Andras Papp; Julit Rapi; Gyorgy Sallai; Matyas Sereg; Ferenc Szaboki; Sandor Timar; Peter Valyi; Gabor Veress.
Israel: Reuven Viskoper; Ben Ben-Valid; Lora Bregman; Henya Brenner; Hedi Feibel; Jos' Fidel; Horla Flandra; Cilia Furman; Uzi Gafter; Jihad Ghanem; Adiv Goldhaber; Israel Hochman; Adrian Iaina; Gennady Katz; Eldad Kisch; Natan Lederman; Israel Lupinski; Alon Margalit; Oscar Minuchin; Joseph Mishael; Olga Moskovich; Shmuel Oren; Ester Paran; Eduardo Podjarni; Joseph Rosenfeld; Eli Rottenstreich; Roza Schneider; Pessah Shvartsman; Eugene Shveydel; Natali Shveydel; Naftali Stern; Alexander Strolovich; Hava Tabenkin; Joshua Weissgarte; Yoram Yagil; Chaim Yosefy; Hoze Zabludowski; David Zacharovitch.
Italy: Alberto Zanchetti; Paolo Alboni; Ettore Ambrosioni; Santo Branca; Alberto Caiazza; Alberto Capra; Agostino Colli; Giuseppe Crippa; Antonio D'Avanzo; Cesare Dell'Oro; Umberto De Martino; Giuseppe De Venuto; Ezio Degli Esposti; Valter Donadon; Stefano Fascetti; Roberto Giovannetti; Giuseppe Licata; Francesco Locatelli; Armando Magagna; Carlo Martines; Andrea Mezzetti; Lucio Mos; Ernesto Mossuti; Angelo Musco; Anna Pasi; Gaetana Palumbo; Carlo Pasotti; Francesco Pellegrini; Sante Donato Pierdomenico; Alessandro Rappelli; Ermanno Rossi; Antonio Salvetti; Mauro Sasdelli; Nicola Scorpiglione; Andrea Semplicini; Umberto Senin; Ernesto Sgarbi; Evandro Tascione; Alvaro Vaccarella; Enrico Vincenzo Valvo; Luigi Vigna.
Mexico: Jorge Herrera Abarca; Pedro Fajardo Campos; Demetrio Kosturakis Garcia; Francisco Javier Gue Martinez; Jose Luis Leiva Pons; Humberto Rodriguez M. Reyes; Raul Gerardo Velasco Sanchez; Eugenio Rusga Zamora; Roberto Bravo Zamudio.
Poland: Alicja M. Kostecka-Pokrysko; Marianna Janion; Krystyna Jaworska; Marek Jedras; Barbara Kusnierz; Michal Ogorek; Wojciech Sodolski; Henryk Swierzy; Eugeniusz Szmatloch; Bozena Raszeja Wanic.
Slovakia: Andrej Dukat; Jozef Gonsorcik; Gabriela Kaliska; Maria Radomska; Alexandr Ruttkay; Rafael Rybar.
Spain: Luis-Miguel Ruilope; Miguel Abad; Jose-Javier Antón; Joaquin Aracil; Pedro Aranda-Lara; Julián Arenas; Andrés Ariza; Juan-Francisco Ayala; Manuel Barcariza; José Barber; M. Jesús Barreda; Manuel-Carlos Barreiro; Joan Bayó; Pedro Cabrera; Carlos Calvo-Gómez; Isable Camé; Jesús Chamorro; Josep Closas; Antonio Coca-Payeras; Natividad Cordero; Rodrigo Córdoba; Juan-Ramón Cuervo; Antoni Dalfó; José-Javier De-Castro; Alberto-J. del-Alamo; V. del-Yerro; Rafael Durá; Angel-Pedro Fernández, Ramón Ferrer; Juan-Eugenio Forcada; Vidal Francisco-Javier; José-Javier Garcia; Blas Gil-Extremera; Manuel Gómez; Apolo Gonzáles; Gonzol Iriarte; Juan-Jose Jimenez; Jose-Ignacio Jimenez; Pedro Jimenez; Jose Luis Llisterri; Jesús López; Carlos López; Juan-Carlos López; Francisco-Javier Lora; Alberto-J. Ma-Jesus; Agustin Martinez; Jesús Martin-Garcia; Fernando Mato; Agustin Minguez; José-Ramón Moliner; Francisco Morales; Manuel Nieto; Javier Nieto-Iglesias; Esther Nuñez; Diego Nuñez; Josefina Oliván-Martinez; Francisca Paniagua; Juan-Carlos Pedrosa; José-Francisco Pensado; Julio Perete; Alvaro Pérez; Pablo Pérez-Luengo; Ascunción Peset; Jaume Plana; M. Angeles Pontes; Miguel-Angel Prieto; Luis-Antonio Ramilla; Salvador Rey; Mercedes Rodriguez; Carlos Rodriguez; Rafael Roldan, Victor Romero; Montserrat Roures; Manuel Royo; Antonio Ruiz; Jaime Ruiz; Aldjandro Salanova; M. Amor Sanchez; Javier Sobrino; Josep Soler; José-Luis Tena; Fernando Torguet; José Torres; Irama Valero; Fernando Veiga; Jose-Félix Zuazagoitia.
Sweden: Lennart Hansson; Valeria Ahgren; Hakan Ahlander; Thomas Angerbjörn; Lars-Erik Bergdahl; Hillevi Blom-Pfeiffer; Mats Boström; Thomas Brydolf; Bo Erik Kristensson; Georg Dahlen; Kent Ekenbratt; Ulla Britt Ericsson; Birger Fagher; Lars Fröberg; Magnus Geirsson; Juha Harju; Thomas Hedner; Christer Höglund; Thomas Hoheisel; Stefan Hofvendahl; Gunilla Johansson; Saima Jönsson; Ingemar Luttu; Hans Nerell; Jan Ostergren; Jan Östergren; Lars Ostling; Anna Maria Ottosson; Martin Rosengren; Aru Sandanam; Sigge Strid; Bengt Svensson; Lars Svensson; Bengt-Olov Tengmark; Thomas Thulin; Claes de Verdier; Per Westerholm.
United Kingdom: Peter Sleight; David Birrell; Mark Blagden; Ian Clark; David Dutchman; Iain Gordon; Nigel Guest; Michael Haughney; David Huggan; Mokshad Kansagra; James Kay; Brian Lennox; Graham Martin; Grant McHattie; Douglas McKeith; Surendra Misra; Peter Mooney; Michael Mutch; Derek Neilson; Mark Reid; Christopher F. Rose; John Ross; Daya Sugar; Pauleen Shearer; Barry Silvert; Roger Snook; Rory C. F. Symons; John Vernon; J. Zachariah.
United States: Henry R. Black; Ali Abdul; Marwan Adjan; Allen B. Adolphe; Jorge Luis Aguilera-Montalvo; Alexander Alvarez; Larry Amacker; Jay Anders; Coleen Andruss; Jose S. Aponte; Jeffrey T. Apter; Peter Arcuri; H. Morgan Ashurst; Gerard P. Aurigemma; Herman Ayvazyan; James Bates; Mark A. Becker; John Bennett; Paul Benson; Lynn Bentson; Joan Benz; James Bergthold; Manick Bhardwaj; Dennis Bloomfield; Zachary T. Bloomgarden; Merle Bolton; Jeffrey L. Boone; Kenneth Boren; Ira R. Braverman; Carlos L. Brown, III; Nate Brown; Robert Burns; Bruce Burtenshaw; David A. Calhoun; James R. Campbell; Barry Caparoso; Mark Capkin; Raymond Carlson; Barry L. Carter; Inge R. Carter; Richard S. Castaldo; Robert Cesarec; C. Kohler Chapmion; Tien C. Cheng; Andrew Chubick; Robert Ciemiega; Mehmood A. Ckan; Irving M. Cohen; Selwyn A. Cohen; Harry T. Colfer; Salvatore Conte; Clinton N. Corder; Marcelo Corpuz; Bruce Corser; Robert E. Cronin; Thomas Crouch; Jairo B. Cruz; Rebecca Dailey; Michael Daniels; Richard H. Davis; Donald M. Denmark; Dolph Martel Denny; Bart G. Denys; Marcus A. DeWood; Edward J. Diamond; Richard Dickstein; Phillip M. Diller; Steven Dorfman; Michael S. Doyle; Steven L. Duckor; Gary Dunkerley; Donald C. Durbeck; M. El Shahawy; Samer Helm Ellahham; William J. Elliott; Georg Emlein; Gary P. Erdy; Michael Famularo; James Farrell; Hebert Fendley; Paul Fenster; James I. Fidelholtz; Justus J. Fiechtner; Larry Fields; Eugene C. Fletcher; Rex W. Force; Carl Franzetti; Francisco Fuentes; Lonnie E. Fuller, Sr; John T. Funai; Marvin Galler; Walter Gaman; Garo S. Garibian; Gumaro Garza; M.R. Gedeon; Michael J. Germain; Steven Glasser; Richard L. Glenn; Sudheer T. Gogte; Ivan L. Goldsmith; Robert J. Goldstein; G. M. Gollapudi; Stephen L. Goss; Atul Goswami; Richard D. Goulah; William F. Graettinger; Ray Graf; Alan Graff; Daniel Gremillion; Clarence Grimm; Colby H. Grossman; Ambrish Gupta; Narendra K. Gupta; Alexander Halkos; Robert J. Harriman; Clyde Harris; Jennifer Hedgepeth; Lynn Helmer; Mario Henriquez; Bradley T. Heppner; Donald K. Hickey; James R. Hill; Matthew Hilmi; Jon Hobson; Judith S. Hochman; Susan Hole; Joanne J. Holland; Lynne Hopkins; Mark Houston; Donald Hunninghake; Carmen D. Irizarry; Sima Issen; Syed Jafri; Avanindra Jain; Oswaldo Jimenez; Kjel Johnson; Wayne H. Kaesemeyer; Richard O. Kamrath; Roy Kaplan; Ronald Karlsberg; H. B. Karunaratne; Gerald Keightley; James Kern; Chet Kessler; Rashid A. Khairi; Vithal Kinhal; Timothy Klein; Gary E. Kolb; Michael J. Koren; Gregory Koshkarian; Marc Kozinn; Jeffrey Kramer; Seth Krauss; Barry Kricsfeld; Steven Kulback; Peter Kurzweil; Niranjan Lal; Victor Lamin; John A. Larry; Gary M. Lattin; Robert Lee; Theodore E. Lefton; Peter M. Lemis; James Lewis; Loren Lipson; Thomas Little; Peter A. Lodewick; Sofia X. Scholar Luisa; Jane Lyssy; Gregory MacDonald; Adrian Magee; Frank Maggiacomo; Craig Maltman; Richard A. Margolin; Charles Margolis; Allan Markus; Barry L. Marmorstein; David G. Marsh; Thomas Martin; Michael Marzec; Daniel Masacarenhas; Brian McCarroll; Mary P. McGowan; Kenneth G. McGrath; Robert D. McInroy; Michael E. McIvor; Timothy Menelly; Franz Messerli; Delbert H. Meyer; Donald W. Middleton, Jr; Felise Milan; Michael Miller; Kelly Mills; Mahendra Mirani; Michael J. Mirro; C. Brendan Montana; Marc Morse; Herbert Moskow; Harvey A. Mossman; William Mroczek; Andrew Muckle; Cynthia Mulrow; Mark A. Munger; Uttam O. L. Munver; David Nash; Jeffrey Newman; Albert Olash, Jr; Roger On; John Ondrejicka; Stephen Ong; Ramin Oskoui; Meenakshi Patel; Tushar C. Patel; Andres Patron; Davita Persaud; Subhash Popli; R. Walter Powell; Rajendra Prasad; William Prechel; Dustan F. Pulle; John Pullman; Gary P. Reams; Jerry A. Reed; Harvey Resnick; Arthus Riba; Ralph W. Richter; Kenneth Rictor; Dennis Riff; Peter Ripley; Terry A. Riske; Daniel Risser; Ernesto Rivera; Jose R. Rivera del Rio; Mohammad Rizwan; Douglas Roberts; Jerry W. Robinson; Thomas Rocco; Daeyoung Roh; Robert S. Rood; Steven J. Rosansky; Herman Rose; Eli M. Roth; Robert Rouchon; Michael R. Rubin; Michael C. Ruddy; Kenneth Russ; Philip Sager; Bradley R. Sakran; Gilbert Salazar; Tariq Saleem; Albert M. Salomon; Raul Sanchez-Ramos; Milton Sands; Francisco A. Santini-Oliveri; Deepak Sant-Ram; Frederick W. Schaerf; Frederick Schaller; Ricky Schneider; John F. Seaworth; Eric Seyferth; Rajnikant Shah; Louis Shane; Jeffrey G. Shanes; Alexander M. M. Shepherd; Charles J. Sigmund; Anthony Silvagni; Stuart J. Simon; Satesh C. Singh; Sudeep Singh; Stan F. Slabic; John Sobolski; William Sokol, Jr; John C. Somberg; Devendra Soni; John Sorensen; Neal B. Sorensen; Vincent Sorrell; Miguel Sosa-Padilla; Daniel Sporn; Allan Stahl; Gregg W. Stone; Henry Stratman; Danny Sugimoto; John E. Sutherland; Louise A. Taber; Addison Taylor; Carmen Texidor; Gerald Timmis; Steven R. Towner; Steven R. Turner; Gregory S. Uhl; Jeffrey R. Unger; Raymond Urbanski; Russell N. Vanhouzen; Jose B. Vazquez-Tanus; Jose L. Vera-Miró; Michael J. Voyack; Wyatt Voyles; Robert C. Watkins, Jr; Mervyn Weerasinghe; Robert Weinstock; Marion R. Wofford; Nathan D. Wong; Laurence G. Yellen; Ralph Yung; Miguel Zabalgoita; Franklin J. Zieve.
Funding/Support: Supported by grants and contracts from G. D. Searle & Co (Skokie, Ill) and Pharmacia (Peapack, NJ).
Role of the Sponsor: Employees of Searle (the original sponsor of CONVINCE) participated in the study design. Employees of Searle's clinical research division monitored the study, along with their contract research organization, Parexel, with whom they shared data collection responsibility. All data analyses, however, were carried out independently of the sponsor by investigators at the University of Minnesota (Minneapolis). The original manuscript and subsequent revisions have been seen and approved by the ranking representative of the sponsor, Dr Anders, who is a coauthor on this article.
Previous Presentation: Presented in part at the 17th Annual Meeting of the Society of Hypertension, New York, NY, May 18, 2002.
Author Affiliations: Department of Preventive Medicine, Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill (Drs Black and Elliott and Ms Lucente); Division of Biostatistics (Mr Grandits and Drs Grambsch and Neaton) and Center for Evidence-Based Medicine (Dr Grimm), University of Minnesota, Minneapolis; Section of Hypertension and Clinical Pharmacology, Department of Medicine, University of Connecticut School of Medicine, Farmington (Dr White); Department of Geriatrics, University of Uppsala, Uppsala, Sweden (Dr Hansson); Centre Hospitalier Universitaire de Québec, Québec (Dr Lacourcière); Department of Medicine, Massachusetts General Hospital, Boston, Mass (Dr Muller); Department of Medicine, Oxford University, and John Radcliffe Hospital, Oxford, England (Dr Sleight); Department of Medicine, State University of New York, and Brookdale Hospital, Brooklyn (Dr Weber); Brigham and Women's Hospital and Harvard Medical School, Boston, Mass (Dr Williams); Statistics Collaborative, Washington, DC (Dr Wittes); Ospedale Maggiore and Istituto Auxologico Italiano and University of Milan, Milan, Italy (Dr Zanchetti); and Clinical Research, Searle Laboratories, Skokie, Ill (Dr Anders).
Dr Hansson is deceased.
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Comparison of Monotherapy Versus Combination Antihypertensive Therapy in Elderly Patients With Essential Hypertension
Antonopoulos et al.
ANGIOLOGY 2008;59:230-235.
ABSTRACT
Clinical Outcomes by Race in Hypertensive Patients With and Without the Metabolic Syndrome: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Wright et al.
Arch Intern Med 2008;168:207-217.
ABSTRACT
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Understanding the Quality Chasm for Hypertension Control in Diabetes: A Structured Review of "Co-maneuvers" Used in Clinical Trials
Naik et al.
J Am Board Fam Med 2007;20:469-478.
ABSTRACT
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Race and Ethnicity in Trials of Antihypertensive Therapy to Prevent Cardiovascular Outcomes: A Systematic Review
Park and Taylor
Ann Fam Med 2007;5:444-452.
ABSTRACT
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Cardiovascular Protection Using Beta-Blockers: A Critical Review of the Evidence
Bangalore et al.
J Am Coll Cardiol 2007;50:563-572.
ABSTRACT
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Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy
Cohen et al.
Neurology 2007;69:668-675.
ABSTRACT
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REPRINT Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention
Rosendorff et al.
Hypertension 2007;50:e28-e55.
FULL TEXT
2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)
Authors/Task Force Members: et al.
Eur Heart J 2007;0:ehm236v1-75.
FULL TEXT
Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention
Rosendorff et al.
Circulation 2007;115:2761-2788.
FULL TEXT
Case Against Angioplasty and Stenting of Atherosclerotic Renal Artery Stenosis
Dworkin and Jamerson
Circulation 2007;115:271-276.
FULL TEXT
Standards of Medical Care in Diabetes--2007
American Diabetes Association
Diabetes Care 2007;30:S4-S41.
FULL TEXT
The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease)
Dzau et al.
Circulation 2006;114:2850-2870.
FULL TEXT
A Primer on the Design, Conduct, and Interpretation of Clinical Trials
Appel
CJASN 2006;1:1360-1367.
ABSTRACT
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Clinical trial design issues: at least 10 things you should look for in clinical trials.
Glasser and Howard
J Clin Pharmacol 2006;46:1106-1115.
ABSTRACT
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Sample size calculation in survival trials accounting for time-varying relationship between noncompliance and risk of outcome event
Li and Grambsch
Clin Trials 2006;3:349-359.
ABSTRACT
Clinical practice. Resistant or difficult-to-control hypertension.
Moser and Setaro
NEJM 2006;355:385-392.
FULL TEXT
Intractable Epistaxis Associated with Topiramate Administration
Page and Bainbridge
The Annals of Pharmacotherapy 2006;40:1462-1465.
ABSTRACT
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Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.
Goldstein et al.
Circulation 2006;113:e873-e923.
ABSTRACT
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Blood Pressure Reduction Is Not the Only Determinant of Outcome
Sever et al.
Circulation 2006;113:2754-2774.
FULL TEXT
Re-examining the efficacy of {beta}-blockers for the treatment of hypertension: a meta-analysis
Khan and McAlister
CMAJ 2006;174:1737-1742.
ABSTRACT
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ASHP Therapeutic Position Statement on the Treatment of Hypertension.
Zillich and Haines
Am J Health Syst Pharm 2006;63:1074-1080.
FULL TEXT
Effect of Antihypertensive Agents on the Development of Type 2 Diabetes Mellitus
Stump et al.
Mayo Clin Proc. 2006;81:796-806.
ABSTRACT
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Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.
Goldstein et al.
Stroke 2006;37:1583-1633.
ABSTRACT
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Role of Diuretics in the Prevention of Heart Failure: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
Davis et al.
Circulation 2006;113:2201-2210.
ABSTRACT
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Statin and beta-blocker therapy and the initial presentation of coronary heart disease.
Go et al.
ANN INTERN MED 2006;144:229-238.
ABSTRACT
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Prognostic Significance for Stroke of a Morning Pressor Surge and a Nocturnal Blood Pressure Decline: The Ohasama Study
Metoki et al.
Hypertension 2006;47:149-154.
ABSTRACT
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Standards of Medical Care in Diabetes-2006
American Diabetes Association
Diabetes Care 2006;29:S4-S42.
FULL TEXT
Treatment of Hypertension: Remaining Issues After the Anglo-Scandinavian Cardiac Outcomes Trial
Kaplan
Hypertension 2006;47:10-13.
FULL TEXT
JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice
Prepared by: British Cardiac Society, British Hype
Heart 2005;91:v1-v52.
FULL TEXT
Calcium Antagonists: Effects on Cardio-Renal Risk in Hypertensive Patients
Nathan et al.
Hypertension 2005;46:637-642.
ABSTRACT
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Persistence with Treatment in Newly Treated Middle-Aged Patients with Essential Hypertension
Perreault et al.
The Annals of Pharmacotherapy 2005;39:1401-1408.
ABSTRACT
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Angiotensin-Converting Enzyme Inhibitors and Calcium Channel Blockers for Coronary Heart Disease and Stroke Prevention
Verdecchia et al.
Hypertension 2005;46:386-392.
ABSTRACT
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Stopping trials early for commercial reasons: the risk-benefit relationship as a moral compass
Iltis
J. Med. Ethics 2005;31:410-414.
ABSTRACT
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Clinical Outcomes in Antihypertensive Treatment of Type 2 Diabetes, Impaired Fasting Glucose Concentration, and Normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Whelton et al.
Arch Intern Med 2005;165:1401-1409.
ABSTRACT
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Effects of Different Blood Pressure-Lowering Regimens on Major Cardiovascular Events in Individuals With and Without Diabetes Mellitus: Results of Prospectively Designed Overviews of Randomized Trials
Blood Pressure Lowering Treatment Trialists' Colla
Arch Intern Med 2005;165:1410-1419.
ABSTRACT
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Outcomes in Hypertensive Black and Nonblack Patients Treated With Chlorthalidone, Amlodipine, and Lisinopril
Wright et al.
JAMA 2005;293:1595-1608.
ABSTRACT
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Recent hypertension trials: Implications and controversies
Williams
J Am Coll Cardiol 2005;45:813-827.
ABSTRACT
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Natural History of Hypertension Subtypes
Verdecchia and Angeli
Circulation 2005;111:1094-1096.
FULL TEXT
Fluid Matters in Choosing Antihypertensive Therapy: A Hypothesis That the Data Speak Volumes
Blankfield
J Am Board Fam Med 2005;18:113-124.
ABSTRACT
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Standards of Medical Care in Diabetes
American Diabetes Association
Diabetes Care 2005;28:S4-S36.
FULL TEXT
Importance of Achieving Lower Blood Pressure in Hypertensive Patients With Diabetes
Brooks and Sowers
Hypertension 2004;44:614-615.
FULL TEXT
Clinical Outcomes in the Diabetes Cohort of the International Verapamil SR-Trandolapril Study
Bakris et al.
Hypertension 2004;44:637-642.
ABSTRACT
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ALLHAT: Setting the Record Straight
Davis et al.
ANN INTERN MED 2004;141:39-46.
ABSTRACT
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Hypertensive Therapy: Part II
Franco et al.
Circulation 2004;109:3081-3088.
FULL TEXT
When Does New Onset Diabetes Resulting From Antihypertensive Therapy Increase Cardiovascular Risk
Bakris and Sowers
Hypertension 2004;43:941-942.
FULL TEXT
Adverse Prognostic Significance of New Diabetes in Treated Hypertensive Subjects
Verdecchia et al.
Hypertension 2004;43:963-969.
ABSTRACT
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Cerebroprotection mediated by angiotensin II: A hypothesis supported by recent randomized clinical trials
Fournier et al.
J Am Coll Cardiol 2004;43:1343-1347.
ABSTRACT
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Economic Implications of Evidence-Based Prescribing for Hypertension: Can Better Care Cost Less?
Fischer and Avorn
JAMA 2004;291:1850-1856.
ABSTRACT
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Blood Pressure and Stroke: An Overview of Published Reviews
Lawes et al.
Stroke 2004;35:1024-1033.
ABSTRACT
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Blood Pressure and Stroke: An Overview of Published Reviews
Lawes et al.
Stroke 2004;35:776-785.
ABSTRACT
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Guidelines for Hypertension: Are Quality-Assurance Measures on Target?
Singer et al.
Hypertension 2004;43:198-202.
ABSTRACT
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Standards of Medical Care in Diabetes
Diabetes Care 2004;27:s15-35.
FULL TEXT
Guidelines for Antihypertensive Treatment: An Update after the ALLHAT Study
Salvetti and Ghiadoni
J. Am. Soc. Nephrol. 2004;15:S51-54.
ABSTRACT
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Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
Chobanian et al.
Hypertension 2003;42:1206-1252.
ABSTRACT
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ADDITIONAL ARTICLES ABSTRACTED IN ACP JOURNAL CLUB
Evid. Based Med. 2003;8:163-163.
FULL TEXT
OTHER ARTICLES NOTED (25 Apr 2003 to 18 Jul 2003)
Evid. Based Nurs. 2003;6:e1-12.
FULL TEXT
Improving Cardiac Outcomes After Noncardiac Surgery
Butterworth and Furberg
Anesth. Analg. 2003;97:613-615.
FULL TEXT
JournalScan
Malik
Heart 2003;89:815-816.
FULL TEXT
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report
Chobanian et al.
JAMA 2003;289:2560-2571.
ABSTRACT
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Another Hypertension Trial: Verapamil vs. Hydrochlorothiazide or Atenolol
JWatch General 2003;2003:1-1.
FULL TEXT
Stopping Medical Research to Save Money: A Broken Pact With Researchers and Patients
Psaty and Rennie
JAMA 2003;289:2128-2131.
FULL TEXT
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